Progressive Supranuclear Palsy (PSP) is a devastating neurodegenerative disorder clinically characterized by vertical gaze palsy, frequent falls, impaired oral functions such as speaking, chewing, and swallowing, and eventual cognitive impairment. Neuropathologically, PSP presents with neurofibrillary tangles (NFTs) and glial tangles comprised of hyperphosphorylated protein tau (htau) in the brainstem, particularly in the pons and medulla. A recent genome-wide association screen (GWAS) for PSP by Schellenberg and collaborators identified a single nucleotide polymorphism within the gene EIF2AK3 as a risk factor for the disease. This gene codes for PERK, an endoplasmic reticulum (ER) membrane protein that functions as a sensor of mis- or unfolded proteins within the ER lumen and is an integral part of the ER's unfolded protein response (UPR). Recently, several groups noted activation of the UPR in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple system atrophy. All of these disorders are characterized by protein aggregates in the brain. Though tau does not traffic through the ER, preliminary results from the Schellenberg lab indicate that the UPR is indeed activated in PSP. Because an allele of the gene encoding PERK is a risk factor for PSP, it is possible that this gene exerts its pathogenic effects through dysregulation of the UPR. The goal of this proposal is to explore this link between the UPR and tau pathogenesis by addressing the following specific aims. Aim 1: Characterize the UPR in PSP and establish the cellular environment in which it is taking place. Aim 1 will employ histological staining techniques as well as Western blotting using PSP post-mortem tissue to demonstrate robust and consistent activation of the UPR as well as co-localization with htau and other protein correlates of neurodegenerative disease. Aim 2: Determine the impact of PERK and the UPR on tau aggregation and spreading in a cell culture model of tauopathy. This novel tau aggregation model was developed by Dr. Virginia M.-Y. Lee's group; training for this aim will include collaboration with Dr. Lee. Aim 2 will employ genetic and phrarmacological manipulations of UPR function and assess effects on tau uptake and aggretation. Aim 3: Determine mechanism by which a genetic change in PERK leads to PSP pathogenesis. Aim 3 will make use of human lymphoblastoid cell lines to determine how protein coding changes in the PERK protein affect its function as part of the UPR. PUBLIC HEALTH RELEVANCE: This proposal aims to establish a pathogenic link between the endoplasmic reticulum unfolded protein response and the neurodegenerative disorder progressive supranuclear palsy (PSP). Insights into the disease-initiating events in PSP will both advance understanding of neurodegenerative tauopathies including Alzheimer's disease and potentially provide therapeutic targets for future drug development.